The regulation of heart rate by beta-adrenergic catecholamines is an important instance of physiological control of membrane excitability. Cardiac fibrillation, on the other hand, represents a breakdown of normal control. The mechanisms of fibrillation and of catecholamine regulation of heart rate are still incompletely understood, partly as a result of the complex geometrical and electrical properties of heart. We propose to take advantage of the fibrillation which spontaneously occurs in denervated mammalian muscle in order to study these two mechanisms at the cellular level. Intracellular recordings from fibrillating muscle fibers have revealed spontaneous fluctuations of membrane protential, called fibrillatory initiating events, which are nonpropogated and arise at a spatially restricted locus termed a "site of origin". Catecholamines have been found to greatly increase initiating event frequency. In order to define the altered electrical properties responsible for fibrillation, we will examine the effects of ionic and pharmacological manipulationson fibrillatory initiating events. The initiating events will be monitored both with a single intracellular microelectrode, inserted at a site or origin, and with a two microelectrode voltage clamp. These studies will yield a description of the role of the Na-K pump and time-varying conductance changes in the fibrillatory electrical activity of denervated muscle. This description will in turn provide the framework for defining the mechanism by which catecholamines control initiating event frequency. To determine whether cyclic AMP mediates the action of catecholamines we will determine whether phosphodiesterase inhibitors cause a leftward shift in the dependence of initiating event frequency on catecholamine dose. The ability of exogenous cyclic AMP to mimic catecholamine action will also be determined. A precise definition of the conditions which give rise to fibrillation in a single cell promises to increase our understanding of factors responsible for fibrillatton in the diseased heart. Similarly, a mechanistic description of catecholamine action at the cellular level should increase our understanding of the mechanisms of heart rate regulation.